1. Field of the Invention
The present invention relates to a novel Streptomyces sp. producing tautomycetin and an immunosuppressant comprising tautomycetin as active ingredient, more specifically, to Streptomyces sp. producing tautomycetin which possesses immunosuppressive or antibacterial activities, a process for preparing tautomycetin from the said microorganism, and an immunosuppressant or immunosuppressive pharmaceutical composition comprising tautomycetin as an active ingredient which suppresses interleukin-2 production, CD69 and interleukin-2 receptor(IL-2R) expression on the cell surface, tyrosine phosphorylation of the proteins related to signal transduction via T-cell receptor(TcR), in a different suppressive mechanism from that of cyclosporin A, and graft rejection in the organ transplantation.
2. Description of the Prior Art
It has been known that the effective suppression of immune response is crucial in organ transplantation because the foreign organ brings about the rejection response by the immune system of the recipient. In this regard, the advent of immunosuppressants allowed the brilliant progress in organ transplantation, the potential remedy for autoimmune diseases, and extensive studies on immune response to foreign organs.
Immunosuppressants have been developed to suppress or attenuate rejection response to foreign organs. Cyclosporin A is the most popular immunosuppressant, which is produced by Tolypocladium inflatum, a soil fungus (see: U.S. Pat. No. 4,117,118). Particularly, immunosuppressants have eased organ transplantation and have been suggested as a potential drug for autoimmune diseases. The immunosuppressants have revealed some drawbacks in the sense that they may have an influence, not specific to T-cells, on the normal healthy organs. For example, it has been reported that cyclosporin A has some untoward effects that cause chronic kidney disease and hypertension after heart transplantation (see: J. E. F. Reynolds, et al., Martindale The Extra Pharmacopoeia, 31st ed., pp. 557-562, Royal Pharmaceutical Society, London, 1996). In this regard, there are strong reasons for exploring and developing novel immunosuppressants with the reduced side effects, and FK-506 was developed as one of the candidate drugs, though it also revealed some severe side effects reported previously (see: Clin. Transplantation, 11:237-242, 1997).
Under the circumstances, the present inventors, based on the significant findings that tautomycetin efficiently suppresses the expression of interleukin-2, the early event of graft rejection, tried to develop a potential immunosuppressant comprising tautomycetin for treating graft rejection and autoimmune diseases.
The present inventors have made efforts to discover a novel immunosuppressant from the soil microorganisms. As a result, the inventors isolated a microbial strain which belongs to Streptomyces sp. from the soil of Halla-mountain in Cheju island in Korea, and obtained tautomycetin from the culture of the said microorganism. Further, they found that the tautomycetin suppresses the production of IL-2, a T-cell proliferating factor, the expression of CD69 and interleukin-2 receptor on the cell surface, and inhibits tyrosine phosphorylation of the proteins related to signal transduction via T-cell receptor(TcR), in a different mechanism from that of cyclosporin A. Finally, they developed an immunosuppressant comprising tautomycetin as an active ingredient for treating graft rejection and autoimmune diseases.
The first object of the present invention is, therefore, to provide Streptomyces sp. producing tautomycetin.
The second object of the invention is to provide a process for preparing tautomycetin from the said microorganism.
The third object of the invention is to provide an immunosuppressant comprising tautomycetin as an active ingredient.
The fourth object of the invention is to provide an immunosuppressive pharmaceutical composition comprising tautomycetin and the other immunosuppressants for a combined treatment.